Novel use of old drug: Anti-rheumatic agent auranofin overcomes imatinib-resistance of chronic myeloid leukemia cells

Xin Chen, Xianping Shi, Xuejun Wang, Jinbao Liu

Abstract


Imatinib mesylate, a specific inhibitor of BCR-ABL tyrosine kinase, is widely used for treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib has emerged as a significant clinical problem. Point mutations, especially T315I mutation, in the kinase domain of BCR-ABL are the most common mechanism of drug resistance to tyrosine kinase inhibitors (TKI), including imatinib. Thus, it is urgent to develop novel therapeutic strategies to overcome TKI-resistance. The anti-rheumatic gold (I) compound Auranofin (AF), was recently approved by US Food and Drug Administration for Phase II clinical trials to treat leukemia. In a recent study, we discovered that AF can selectively inhibit 19S proteasome-associated deubiquitinases (UCHL5 and USP14), which mediates its anticancer effects. More recently studies we have shown that AF inhibits the growth of both Bcr-Abl wild-type cells and IM-resistant Bcr-Abl-T315I mutation cells in vitro and in vivo. AF-induced Bcr-Abl downregulation is associated with diminished mRNA expression and caspase-dependent Bcr-Abl cleavage. More importantly, we unraveled that AF cytotoxicity is mediated by proteasome inhibition rather than previously suspected reactive oxygen species (ROS) generation. These findings support that AF overcomes IM-resistance through Bcr/Abl-dependent and -independent mechanisms, identifying a potentially new strategy for cancer treatment.


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DOI: http://dx.doi.org/10.14800/ccm.415

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Copyright (c) 2014 Xin Chen, Xianping Shi, Xuejun Wang, Jinbao Liu

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